Pd-smopex-111: A new catalyst for Heck and Suzuki cross-coupling reactions

Article abstract of DOI:10.1021/op7000657

Smopex-111, a commercially available metal-scavenging styryl thiol-grafted polyolefin fiber was treated with palladium acetate giving a reagent with a palladium loading of 4.4-4.7 (wt %). The Pd-Smopex-111 thus generated was found to be a highly active catalyst for Heck and Suzuki coupling reactions and was found to be reusable with negligible leaching of palladium.

Full text of DOI:10.1021/op7000657

Organic Process Research & Development 2007, 11, 769−772
Technical Notes
Pd-Smopex-111: A New Catalyst for Heck and Suzuki Cross-Coupling
Reactions
Xinglong Jiang, Joseph Sclafani, Kapa Prasad,* Oljan Repicˇ, and Thomas J. Blacklock
Process Research & DeVelopment, NoVartis Pharmaceuticals Corporation, One Health Plaza, East HanoVer,
New Jersey 07936, U.S.A.
Table 1. Palladium loading on Smopex-111 in different
solvents
Abstract:
Smopex-111, a commercially available metal-scavenging styryl
thiol-grafted polyolefin fiber was treated with palladium acetate
giving a reagent with a palladium loading of 4.4-4.7 (wt %).
The Pd-Smopex-111 thus generated was found to be a highly
active catalyst for Heck and Suzuki coupling reactions and was
found to be reusable with negligible leaching of palladium.
Pd-Smopex-111
solvent(s)
THF
Pd loading (wt %)
0.75
toluene
EtOH
EtOH (70 °C)
4.4 to 4.7
2.4
3
materials such as carbon,6 zeolites,7 silica,8 sepiolites,9,10
polyionic gels,11 hydrotalcite,12 core-shell block copoly-
mers,13 and triphenylphosphinated polystyrene beads. 14 The
palladium level in the product was lower in these systems
when compared to homogeneous palladium catalysts; how-
ever, in many cases, it was still above the limit set for active
pharmaceutical ingredients. With our recent successful
experience in using the Smopex family15 of absorbents for
removing residual palladium from products derived from
palladium-catalyzed reactions, we were intrigued by the
possibility of using the complex formed between Pd and
Smopex-111 in organic reactions.
Smopex-111, commercially available from Johnson Mat-
they, is a styryl thiol-grafted polyolefin fiber. It is a new
metal-scavenging system for the recovery of low levels of
precious metals from catalytic reactions. Binding to pal-
ladium is very efficient due to active groups located almost
exclusively on the surface of the fiber, making this material
very attractive for removing palladium from processes. In
keeping with our ongoing objectives to develop practical and
economical processes for industrial applications, we sought
to use palladium adsorbed on Smopex-111 (Pd-Smopex-
111) as a catalyst in Suzuki and Heck cross-coupling
reactions.
Introduction
Palladium-catalyzed cross-coupling reactions such as
Suzuki and Heck have been demonstrated to be some of the
most powerful methods for constructing carbon-carbon
bonds.1-3 In general, a homogeneous palladium catalyst and
ligand are required for these reactions. However, cross-
coupling reactions with homogeneous palladium have several
shortcomings such as limited reusability, which impacts cost
and palladium contamination in the product. Removal of
residual palladium4 provides a challenging task for chemists
in the pharmaceutical industry to reduce the palladium to a
level that satisfies specifications required by regulators.
Many methods have been introduced recently to address
the palladium contamination issue, which include palladium-
containing perovskites,5 palladium supported on various
(1) For leading references, see: (a) Suzuki, A. In Handbook of Organopalla-
dium Chemistry for Organic Synthesis; Negishi, E.-I., Ed.; Wiley-
Interscience: New York, 2002. (b) Miyaura, N. In Metal-Catalyzed Cross-
Coupling Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: New
York, 2004. (c) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-
2483.
(2) For recent reviews, see: (a) Prashad, M. Top. Organomet. Chem.
(Organometallics in Process Chemistry) 2004, 6, 181-203 and references
therein. (b) Dupont, J.; Pfeffer, M.; Spencer, J. Eur. J. Inorg. Chem. 2001,
1917-1927. (c) Albrecht, M.; van Koten, G. Angew. Chem., Int. Ed. 2001,
40, 3750-3781. (d) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000,
100, 3009-3066. (e) Farina, V. AdV. Synth. Catal. 2004, 346, 1553-1582.
(3) (a) Heck, R. F. Acc. Chem. Res. 1979, 12, 146-151. (b) de Vries, J. G.
Dalton Trans. 2006, 421-429.
(9) Corma, A.; Garcia, H.; Leyva, A.; Primo, A. Appl. Catal., A 2004, 257,
77-83.
(4) Garrett, C. E.; Prasad, K. AdV. Synth. Catal. 2004, 346, 889.
(5) (a) Smith, M. D.; Stephan, A. F.; Ramarao, C.; Brennan, P. E.; Ley, S. V.
Chem. Commun. 2003, 2652-2653. (b) Andrews, S. P.; Stephan, A. F.;
Tanaka, H.; Ley, S. V.; Smith, M. D. AdV. Synth. Catal. 2005, 347, 647-
654.
(6) Dantas Ramos, A. L.; da Silva Alves, P.; Aranda, D. A. G.; Schmal, M.
Appl. Catal., A 2004, 277, 71.
(7) Okumura, K.; Nota, K.; Yoshida, K.; Niwa, M. J. Catal. 2005, 231, 245.
(8) (a) Crudden, C. M.; Sateesh, M.; Lewis, R. J. Am. Chem. Soc. 2005, 127,
10045-10050 and references therein. (b) Papp, A.; Galbacs, G.; Molnar,
A. Tetrahedron Lett. 2005, 46, 7725-7728.
(10) Shimizu, K.; Maruyama, R.; Komai, S.; Kodama, T.; Kitayama, Y. J. Catal.
2004, 227, 202-209.
(11) Thiot, C.; Schmutz, M.; Wagner, A.; Mioskowski, C. Angew. Chem., Int.
Ed. 2006, 45, 2868-2871.
(12) Ruiz, J. R.; Jimenez-Sanchidrian, C.; Mora, M. Tetrahedron 2006, 62,
2922-2926.
(13) Okamoto, K.; Akiyama, R.; Kobayashi, S. Org. Lett. 2004, 6, 1987.
(14) Shieh, W.-S.; Shekhar, R.; Blacklock, T.; Tedesco, A. Synth. Commun.
2002, 32, 1059-1067.
(15) Johnson Matthey Catalysts, The Catalyst Technical Handbook; Johnson
Matthey Co.: London, UK, 2005; p 20.
10.1021/op7000657 CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/12/2007
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Scheme 1. Heck reaction of Ar-Br with alkyl acrylate
mixture at 120 °C for 20-24 h, the reaction mixture was
cooled, and the catalyst was filtered. The filtrate was
extracted with ethyl acetate and washed with water. The
crude product was obtained by evaporation of ethyl acetate
to dryness. The palladium content of this crude mixture was
analyzed before further purification by column chromatog-
raphy on silica gel.
As depicted in Table 2, the catalyst demonstrated good
activity. All substrates either with electron-donating or
electron-withdrawing functional groups afforded good yields.
In entry 2, hydrolysis of the ethyl ester was observed under
the basic condition, and 13% of the corresponding acid was
isolated. The treatment of bromobenzene with acrylonitrile
(entry 5) also gave a low conversion due to the low boiling
point of the reaction mixture containing acrylonitrile. The
palladium content of the reaction mixture after filtration of
the catalyst, as demonstrated in Table 2, was below 10 ppm,
which indicated that the Smopex-111 has a strong affinity
for palladium even under harsh reaction conditions. The
results clearly demonstrate this catalyst may have practical
utility.
Preparation of Pd-Smopex-111
Palladium can be easily loaded onto Smopex-111 by
stirring a prefiltered solution of palladium acetate and
Smopex-111 at elevated temperature. After filtration and
washing, the complex was dried and the content of palladium
confirmed by weight and analysis. As demonstrated in Table
1, palladium content depended on the solvent system used.
For example, palladium loading on Smopex-111 was 0.75%
(by weight) using THF, while a range of 4.4-4.7% palladium
loading was obtained when toluene was used as the solvent.
More polar solvents such as ethanol and N-methylpyrroli-
dinone (NMP) afforded 1.53 and 2.4% palladium loading,
respectively. On the basis of the amount of palladium loaded
on Smopex-111, the complex obtained from toluene was
selected for further use.
Heck Reaction
The Heck reaction shown in Scheme 1, was conducted
by reaction of aryl bromide with alkyl acrylate (1.3 equiv)
and a base (1.3 equiv) in the presence of Pd-Smopex-111
catalyst (2.5% by weight) in NMP. After heating the reaction
Suzuki Reaction
The Pd-Smopex-111 complex was also successful when
employed in Suzuki couplings. Coupling of aryl bromides
with phenylboronic acid occurred readily with Pd-Smopex-
Table 2. Heck reactiona using Pd-Smopex-111
a Reaction conditions: 10 mmol of substrate, 13 mmol of Heck acceptor, 0.8 g of Pd-Smopex (2.5 wt % of Pd with respect to the substrate), 10 mL of NMP, 118
°C, 16-24 h.
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Table 3. Suzuki coupling reactions using phenylboronic acid and Pd-Smopex-111
a wt % of Pd with respect to the substrate. b 5% 2-(di-tert-butylphosphino)biphenyl added.
Table 4. Suzuki reactions with phenylboronic acid using water as a solvent
Scheme 2. Recycling of the catalyst
111 using K3PO4 as the base and a water/toluene mixture
(Table 3). Only in the case of chloroacetophenone (entry 6)
was a ligand required for coupling to occur. No coupling
was observed in the absence of ligand. Interestingly, even
in this case, leaching was minimal. Substrates containing
electron-donating groups (entry 4) required twice the amount
of catalyst typically employed.
We also explored water alone as a solvent for water-
soluble substrates. We were pleased to find that the palladium
leaching was not significant (Table 4, entry 1) under these
conditions. It is unclear why the 3-bromobenzoic acid
derivative experienced higher Pd contamination.
Recycling of the Catalyst
Recycling of the Pd-Smopex-111 was also explored
(Scheme 2). In each iteration, the catalyst from the reaction
was filtered off, washed, and reused without concern for
exposure to air. As is evident from the data (Table 5),
palladium leaching from the catalyst is negligible with each
cycle. No noticeable loss of activity was observed as noted
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Table 5
General Procedure for Heck Couplings with Pd-
Smopex-111 in N-Methyl-2-pyrrolidione (NMP). To a N2-
purged 50-mL round-bottomed flask were added 4-bromo-
acetophenone (2.0 g, 10 mmol), butyl acrylate (1.68 g, 13
mmol), N,N-diisopropylethylamine (1.68 g, 13 mmol), Pd-
Smopex-111 (0.8 g , 2.5%), and N-methyl-2-pyrrolidinone
(NMP, 10 mL). The resulting mixture was heated at 118 °C
for 16 h, and the reaction was monitored by HPLC. After
the completion of the reaction, the mixture was cooled to
room temperature and filtered through Celite. The filtrate
was diluted with 50 mL of ethyl acetate and washed with
two 10-mL portions of water. The organic layer was dried
over MgSO4 and concentrated to dryness under pressure.
General Procedure for Suzuki Couplings with Pd-
Smopex-111 in Toluene. To a N2-purged 25-mL round-
bottomed flask were added 4-bromoacetophenone (500 mg,
2.51 mmol), phenyl boronic acid (389 mg, 3.19 mmol),
K3PO4‚H2O (1.15 g, 5.0 mmol), Pd-Smopex-111 (140 mg,
2.5%), toluene (4 mL). and water (1 mL). The mixture was
heated to 95 °C for 2.5 h. Upon completion of the reaction,
the mixture was filtered through Celite, and the filtered solids
were washed with 40 mL of toluene in two portions followed
by 40 mL of water in two portions. The aqueous layer was
discarded, and the organic layer was dried with Mg2SO4.
The organic layer was concentrated and placed in a vacuum
oven (50 mbar, 40 °C) for 12 h to give a white solid (475
mg, 97%) which was examined for Pd. The resulting solid
was found to be pure by HPLC and NMR.
General Procedure for Suzuki Couplings with Pd-
Smopex-111 in Water. To a N2-purged 25-mL round-
bottomed flask were added 4-bromophenylacetic acid (1.0
g, 4.64 mmol), phenyl boronic acid (0.74 g, 6.07 mmol),
K2CO3 (1.92 g, 13.9 mmol), Pd-Smopex-111 (280 mg,
2.5%), and water (9.3 mL). The mixture was heated at 98
°C for 2.5 h. Upon completion of the reaction, the mixture
was filtered through Celite, and the filtered cake was washed
with 40 mL of water in two portions. The aqueous layer
was extracted with 40 mL of ethyl acetate in two portions.
The aqueous layer was acidified by adding 30 mL of 1 N
HCl to give a white precipitate. The solid was collected by
vacuum filtration, washed with 10 mL of water, and placed
in a vacuum oven (50 mbar, 40 °C) for 12 h. The resulting
white solid (928 mg, 91%) was examined for Pd. The
resulting solid was pure by HPLC and NMR.
cycle
1
2
3
4
Pd leaching (ppm)
conversion (%)
<1.0
100
1.4
100
1.7
100
4.1
100
by reproducible reaction times for each cycle. In all of the
four cycles, the reaction was complete in 2.5 h.
In conclusion, Pd-Smopex-111 was found to be an
interesting catalyst for both Suzuki and Heck cross-coupling
reactions. The catalyst system is recyclable with no noticeable
change in activity. Isolation of the catalyst involves simple
filtration of the solid-supported Pd. In cases were the
substrate was soluble, water was used as the solvent. Both
electron-donating and electron-withdrawing groups on the
bromo-arene are tolerated.
Experimental Section
All chemicals were obtained from commercial suppliers
and used without further purification. H and 13C NMR
1
spectra were recorded at 500 or 300 and at 125 or 75 MHz
respectively, in CDCl3 unless otherwise noted. Proton and
carbon chemical shifts are expressed in ppm relative to
internal tetramethylsilane; coupling constants (J) are ex-
pressed in Hertz. Melting points were measured on a Bu¨chi
535 melting point apparatus. Pd contents were measured by
ICP analysis method at Novartis or in Robertson Microlit
Lab after the reaction mixture was filtered, then extracted
with ethyl acetate, washed with water, dried, and concen-
trated to dryness.
General Procedure for the Preparation of Pd-Smopex-
111. To a N2-purged three-necked round-bottomed flask fitted
with an overhead stirrer and an internal thermometer were
added Pd(OAc)2 (2.0 g, 8.92 mmol) and toluene (100 mL).
The mixture was heated to 70 °C internally for 15 min to
give a solution with traces of suspended particles present.
The insoluble material was filtered off using a syringe filter,
and the resulting solution was placed in a clean, inerted three-
necked, round-bottomed flask fitted with an overhead stirrer
and an internal thermometer. To the palladium acetate
solution was added Smopex-111 (18.0 g) and the mixture
heated to 70 °C internally for 5 h. After heating, the mixture
was stirred at 17 °C for 12 h. The mixture was filtered, and
the solids were washed twice with 100 mL of toluene. The
isolated solid was placed in a vacuum oven (50 mbar, 40
°C) for 12 h. The resulting brown solid weighed 19.92 g
and contained 4.32% Pd by weight based on the ICP analysis
of the digested complex.
Received for review March 15, 2007.
OP7000657
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